The present proposal deals with aspects of cardiorespiratory integration, a continuing theme of this laboratory for more than 20 years. The unifying concept is that the heart, lungs and blood constitute a coordinated system for the uptake of oxygen from the air in accord with tissue needs at rest and during exercise, that the apparatus is organized to operate efficiently and designed to cope with requirements during maximal exertion. A similar set of considerations could be applied to the elimination of carbon dioxide from the body. Over the years, individual elements of the system have been examined separately to determine their characteristics and behavior, to assess how they are incorporated into the entire cardiorespiratory apparatus, and to learn how the coordinated behavior of the system is effected. One important by-product of this interest has been the exploration of the circulation of water (and macromolecules) from pulmonary capillary plasma to lymph and the appreciation of how this "third circulation (in addition to pulmonary and bronchial) acts to preserve gas exchange in the face of potential flooding of its surfaces. Another rewarding aspect has been the continuing concern with the control of breathing: emphasis has now shifted from the original preoccupation with the effects of chemical stimuli on the ventilation to the current interest in the neurophysiological contributions to the ventilatory drive. Also, in line with our comparative biological approach to complicated integrations in terrestrial animals and humans, research on ventilatory control continues on the lungfish, the first animal to move from life in water to residence on land. A similar progression of our research is exemplified by our studies of the pulmonary circulation: from the original concerns with pulmonary blood pressures, flow, volumes and regulatory mechanisms, attention now is directed at water and macromolecular exchanges in the pulmonary microcirculation, with particular reference to structural-functional relationships. As a result, during the past few years, we have been able to characterize certain aspects of the alveolar capillary barrier according to macromolecular sieving. But, in addition, recognizing that this categorization is incomplete, were have begun to explore systematically the effect of electrostatic charges on endothelium, blood constituents and interstitial space on the movement of macromolecules from plasma to the perivascular spaces. An important point of conjunction between the ventilatory and plasma-interstitial-lymph systems is the sensation of dyspnea and the receptors and pathways that mediate this sensation.